scholarly journals The mTORC1-mediated activation of ATF4 promotes protein and glutathione synthesis downstream of growth signals

2020 ◽  
Author(s):  
Margaret E. Torrence ◽  
Michael R. MacArthur ◽  
Aaron M. Hosios ◽  
Alexander J. Valvezan ◽  
John M. Asara ◽  
...  
Keyword(s):  
Protein Synthesis ◽  
Target Genes ◽  
Amino Acid Uptake ◽  
Acid Uptake ◽  
Glutathione Synthesis ◽  
Downstream Target ◽  
Mechanistic Target Of Rapamycin ◽  
Transcriptional Changes ◽  
Growth Promoting ◽  
Established Role

AbstractThe mechanistic target of rapamycin complex 1 (mTORC1) stimulates a coordinated anabolic program in response to growth-promoting signals. Paradoxically, recent studies indicate that mTORC1 can activate the adaptive stress-responsive transcription factor ATF4 through mechanisms distinct from its canonical induction by the integrated stress response (ISR). However, how ATF4 functions in response to these distinct modes of regulation and its broader role as a downstream target of mTORC1 are unknown. Therefore, we directly compared ATF4-dependent transcriptional changes induced upon activation of mTORC1 or the ISR. The mTORC1-ATF4 pathway stimulated the expression of only a subset of the ATF4 target genes stimulated by the ISR, including genes involved in amino acid uptake, synthesis, and tRNA charging. We demonstrate that ATF4 is a metabolic effector of mTORC1 involved in both its established role in promoting protein synthesis and in a previously unappreciated function for mTORC1 in stimulating cellular cystine uptake and glutathione synthesis.

scholarly journals The mTORC1-mediated activation of ATF4 promotes protein and glutathione synthesis downstream of growth signals

eLife ◽  
2021 ◽  
Vol 10 ◽  
Author(s):  
Margaret E Torrence ◽  
Michael R MacArthur ◽  
Aaron M Hosios ◽  
Alexander J Valvezan ◽  
John M Asara ◽  
...  
Keyword(s):  
Target Genes ◽  
Human Cancer ◽  
Amino Acid Uptake ◽  
Acid Uptake ◽  
Glutathione Synthesis ◽  
Human Cancer Cell Lines ◽  
Downstream Target ◽  
Mtorc1 Signaling ◽  
Transcriptional Changes ◽  
Established Role

The mechanistic target of rapamycin complex 1 (mTORC1) stimulates a coordinated anabolic program in response to growth-promoting signals. Paradoxically, recent studies indicate that mTORC1 can activate the transcription factor ATF4 through mechanisms distinct from its canonical induction by the integrated stress response (ISR). However, its broader roles as a downstream target of mTORC1 are unknown. Therefore, we directly compared ATF4-dependent transcriptional changes induced upon insulin-stimulated mTORC1 signaling to those activated by the ISR. In multiple mouse embryo fibroblast (MEF) and human cancer cell lines, the mTORC1-ATF4 pathway stimulated expression of only a subset of the ATF4 target genes induced by the ISR, including genes involved in amino acid uptake, synthesis, and tRNA charging. We demonstrate that ATF4 is a metabolic effector of mTORC1 involved in both its established role in promoting protein synthesis and in a previously unappreciated function for mTORC1 in stimulating cellular cystine uptake and glutathione synthesis.

scholarly journals Action of growth hormone in vitro on the net uptake and incorporation into protein of amino acids in muscle from intact rabbits given protein-deficient diets

1976 ◽  
Vol 35 (1) ◽  
pp. 1-10 ◽  
Author(s):  
M. R. Turner ◽  
P. J. Reeds ◽  
K. A. Munday
Keyword(s):  
Amino Acids ◽  
Growth Hormone ◽  
Protein Synthesis ◽  
Amino Acid ◽  
De Novo ◽  
Amino Acid Uptake ◽  
Acid Uptake ◽  
Amino Acid Incorporation ◽  
Acid Incorporation

1. Net amino acid uptake, and incorporation into protein have been measured in vitro in the presence and absence of porcine growth hormone (GH) in muscle from intact rabbits fed for 5 d on low-protein (LP), protein-free (PF) or control diets.2. In muscle from control and LP animals GH had no effect on the net amino acid uptake but stimulated amino acid incorporation into protein, although this response was less in LP animals than in control animals.3. In muscle from PF animals, GH stimulated both amino acid incorporation into protein and the net amino acid uptake, a type of response which also occurs in hypophysectomized animals. The magnitude of the effect of GH on the incorporation of amino acids into protein was reduced in muscle from PF animals.4. The effect of GH on the net amino acid uptake in PF animals was completely blocked by cycloheximide; the uptake effect of GH in these animals was dependent therefore on de novo protein synthesis.5. It is proposed that in the adult the role of growth hormone in protein metabolism is to sustain cellular protein synthesis when there is a decrease in the level of substrate amino acids, similar to that which occurs during a short-term fast or when the dietary protein intake is inadequate.

scholarly journals Action of insulin and growth hormone on protein synthesis in muscle from non-hypophysectomized rabbits

1971 ◽  
Vol 125 (2) ◽  
pp. 515-520 ◽  
Author(s):  
P. J. Reeds ◽  
K. A. Munday ◽  
M. R. Turner
Keyword(s):  
Amino Acids ◽  
Growth Hormone ◽  
Protein Synthesis ◽  
Amino Acid ◽  
Incubation Medium ◽  
Amino Acid Uptake ◽  
Diaphragm Muscle ◽  
Acid Uptake

The separate effects of insulin and growth hormone on the uptake and incorporation of five amino acids into diaphragm muscle from non-hypophysectomized rabbits has been examined. Both growth hormone and insulin, when present in the medium separately, stimulated the incorporation into protein of the amino acids, leucine, arginine, valine, lysine and histidine. Insulin also stimulated amino acid uptake, but growth hormone did not. When insulin and growth hormone were present in the incubation medium together, the uptake and incorporation of valine, the only amino acid studied under these conditions, tended to be greater than the sum of the separate effects of the two hormones.

scholarly journals Transforming Potential of the Herpesvirus Oncoprotein MEQ: Morphological Transformation, Serum-Independent Growth, and Inhibition of Apoptosis

1998 ◽  
Vol 72 (1) ◽  
pp. 388-395 ◽  
Author(s):  
Juinn-Lin Liu ◽  
Ying Ye ◽  
Lucy F. Lee ◽  
Hsing-Jien Kung
Keyword(s):  
Protein Synthesis ◽  
Target Genes ◽  
Rapid Development ◽  
Fibroblast Cell ◽  
Protein Synthesis Inhibitor ◽  
Morphological Transformation ◽  
Synthesis Inhibitor ◽  
Necrosis Factor Alpha ◽  
Downstream Target ◽  
T Cell Lymphomas

ABSTRACT Marek’s disease virus (MDV) induces the rapid development of overwhelming T-cell lymphomas in chickens. One of its candidate oncogenes, meq (MDV Eco Q) which encodes a bZIP protein, has been biochemically characterized as a transcription factor. Interestingly, MEQ proteins are expressed not only in the nucleoplasm but also in the coiled bodies and the nucleolus. Its novel subcellular localization suggests that MEQ may be involved in other functions beyond its transcriptional potential. In this report we show that MEQ proteins are expressed ubiquitously and abundantly in MDV tumor cell lines. Overexpression of MEQ results in transformation of a rodent fibroblast cell line, Rat-2. The criteria of transformation are based on morphological transfiguration, anchorage-independent growth, and serum-independent growth. Furthermore, MEQ is able to distend the transforming capacity of MEQ-transformed Rat-2 cells through inhibition of apoptosis. Specifically, MEQ can efficiently protect Rat-2 cells from cell death induced by multiple modes including tumor necrosis factor alpha, C2-ceramide, UV irradiation, and serum deprivation. Its antiapoptotic function requires new protein synthesis, as treatment with a protein synthesis inhibitor, cycloheximide, partially reversed MEQ’s antiapoptotic effect. Coincidentally, transcriptional induction of bcl-2 and suppression of bax are also observed in MEQ-transformed Rat-2 cells. Taken together, our results suggest that MEQ antagonizes apoptosis through regulation of its downstream target genes involved in apoptotic and/or antiapoptotic pathways.

Protein and energy metabolism in the pre-implantation cattle embryo

2001 ◽  
Vol 26 (2) ◽  
pp. 443-446 ◽  
Author(s):  
D.G. Morris ◽  
P. Humpherson ◽  
H.J. Leese ◽  
J.M. Sreenan
Keyword(s):  
Amino Acids ◽  
Protein Synthesis ◽  
Amino Acid ◽  
Energy Metabolism ◽  
Metabolic Rate ◽  
Protein Content ◽  
Amino Acid Uptake ◽  
Acid Uptake ◽  
Glucose Utilisation ◽  
Embryonic Loss

AbstractThere is no information on the metabolism of the cattle embryo during the period from day 8 to 16 a period of greatest embryonic loss. In this study the rate of protein synthesis and phosphorylation was measured in 13 to 15 day old cattle embryos. The rate of glucose utilisation and amino acid uptake/efflux by day 14 to 16 embryos was also measured. Protein synthesis and phosphorylation activity when expressed per unit of protein decreased with increasing embryo size and age. Similarly the rate of glucose utilisation was greatest for the earlier day 14 embryos. Embryos differed in their requirement for different amino acids. The pattern of uptake/efflux was similar to that of the earlier day 7 embryo. This study suggests that the metabolic rate of cattle embryos expressed per unit of protein content tends to decrease with increasing age and size from the initial burst of activity at day 13 around the time that expansion of the embryo begins.

Follicle-stimulating hormone administration affects amino acid metabolism in mammalian oocytes†

2019 ◽  
Vol 101 (4) ◽  
pp. 719-732 ◽  
Author(s):  
Anna Tetkova ◽  
Andrej Susor ◽  
Michal Kubelka ◽  
Lucie Nemcova ◽  
Denisa Jansova ◽  
...  
Keyword(s):  
Protein Synthesis ◽  
Amino Acid ◽  
Follicle Stimulating Hormone ◽  
Amino Acid Uptake ◽  
Acid Uptake ◽  
Fsh Receptor ◽  
Cytoplasmic Maturation ◽  
Vitro Effect ◽  
Stimulating Hormone

Abstract Culture media used in assisted reproduction are commonly supplemented with gonadotropin hormones to support the nuclear and cytoplasmic maturation of in vitro matured oocytes. However, the effect of gonadotropins on protein synthesis in oocytes is yet to be fully understood. As published data have previously documented a positive in vitro effect of follicle-stimulating hormone (FSH) on cytoplasmic maturation, we exposed mouse denuded oocytes to FSH in order to evaluate the changes in global protein synthesis. We found that dose-dependent administration of FSH resulted in a decrease of methionine incorporation into de novo synthesized proteins in denuded mouse oocytes and oocytes cultured in cumulus-oocyte complexes. Similarly, FSH influenced methionine incorporation in additional mammalian species including human. Furthermore, we showed the expression of FSH-receptor protein in oocytes. We found that major translational regulators were not affected by FSH treatment; however, the amino acid uptake became impaired. We propose that the effect of FSH treatment on amino acid uptake is influenced by FSH receptor with the effect on oocyte metabolism and physiology.

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